The adenomatous polyp is an almost essential intermediate in the progression of normal intestinal epithelium to gastrointestinal cancer. Strong support for this view has been provided by clinical and molecular genetic studies of the inherited syndrome, adenomatous polyposis coli (APC), and of sporadic colorectal polyps, thus providing one of the most important windows into the pathogenesis of colon cancer. In pursuing the molecular basis of APC, we identified a tumor suppressor gene, APC, that is now recognized as a primary step in polyp development and progression to cancer. The theme of this Program focuses on the adenomatous polyp: laboratory analysis of its genetic origins, and the molecular and cellular biology of the polyp as a precursor to cancer. Studies of the cellular and molecular changes resulting from mutation of APC form the basis for Project one; our investigations will address functional aspects of the APC protein with regard to its subcellular localization, post-translational regulation and novel binding partners. The second will employ cellular, molecular, biological and genetic approaches to examine the role of cyclooxygenase, a key target of effective chemopreventative agents, in the genesis and progression of adenomatous polyps. Project 3 examines the molecular mechanisms connecting mutations in genes encoding DNA mismatch repair enzymes, which are implicated in a separate form of inherited colon cancer, with observed changes in colon epithelial cells. The fourth seeks to determine the genetic basis for heterogeneity in an attenuated form of the APC syndrome. The fifth project is designed to identify the basis for familial forms of colon cancer that cannot be attributed to mutations in APC or mismatch repair genes. Our preliminary results suggests that several unidentified genes likely account for additional forms of familial colon cancer; in the course of this project, we will identify affected families and carry out initial linkage studies. The Program will support administrative, clinical, tissue procurement and cell culture cores. Use of these core facilities is widespread, as there is extensive interaction among the various projects. In summary, this Program provides an integrated approach to the major precursor to colon cancer, the adenomatous polyp. Our approach is multi-disciplinary with interactive Projects based on molecular and cellular biology, genetics, and clinical characterization. These studies of the adenomatous polyp of the colon offer an unusual and important opportunity for the discovery of new approaches to the prevention of colon cancer through detection and elimination of its precursor, the adenomatous polyp.